1-111780320-A-G

Variant names:

• chr1-111780320-A-G
• rs765435324
• NM_001378969.1:c.1372-6T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001378969.1(KCND3):​c.1372-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,558,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: KCND3 NM_001378969.1 splice_region, intron
• Scores: Splicing: ADA: 0.00003007
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.173
• Publications: 0 publications found

Genes affected

KCND3 (HGNC:6239): (potassium voltage-gated channel subfamily D member 3) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]

KCND3 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P
• spinocerebellar ataxia type 19/22

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
• Brugada syndrome 9

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-111780320-A-G is Benign according to our data. Variant chr1-111780320-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 533727.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378969.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	NM_001378969.1	MANE Select	c.1372-6T>C		splice_region intron	N/A	NP_001365898.1	Q9UK17-1
	KCND3	NM_004980.5		c.1372-6T>C		splice_region intron	N/A	NP_004971.2
	KCND3	NM_001378970.1		c.1372-6T>C		splice_region intron	N/A	NP_001365899.1	Q9UK17-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	ENST00000302127.5	TSL:5 MANE Select	c.1372-6T>C		splice_region intron	N/A	ENSP00000306923.4	Q9UK17-1
	KCND3	ENST00000315987.6	TSL:1	c.1372-6T>C		splice_region intron	N/A	ENSP00000319591.2	Q9UK17-1
	KCND3	ENST00000369697.5	TSL:1	c.1372-6T>C		splice_region intron	N/A	ENSP00000358711.1	Q9UK17-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000243 AC: 4 AN: 164890 AF XY: 0.0000115

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000634

Gnomad NFE exome AF: 0.0000306

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 26 AN: 1406882 Hom.: 0 Cov.: 31 AF XY: 0.0000216 AC XY: 15 AN XY: 694524

African (AFR) AF: 0.00 AC: 0 AN: 32150

American (AMR) AF: 0.0000273 AC: 1 AN: 36620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25246

East Asian (EAS) AF: 0.00 AC: 0 AN: 36954

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79742

European-Finnish (FIN) AF: 0.0000201 AC: 1 AN: 49848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.0000213 AC: 23 AN: 1082322

Other (OTH) AF: 0.00 AC: 0 AN: 58334

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74288

African (AFR) AF: 0.0000242 AC: 1 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Spinocerebellar ataxia type 19/22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.49
DANN	Benign	0.66
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0040
Splicevardb		1.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs765435324;

hg19: chr1-112322942;